Organophosphorus (OP) agents have been used as both pesticides and chemical warfare agents for most of the past century (Mercey, G., et al., Acc. Chem. Res. 2012, 45, 756; and Jokanovic, M.; Prostran, M. Curr. Med. Chem. 2009, 16, 2177). Pesticides based on phosphate or thiophosphate agents (e.g. parathion, diazinon, or malathion) are or have been used in domestic and commercial agriculture to protect crops from a variety of destructive species. Despite numerous efforts to ban or limit the use of OP pesticides, their continued use results in over 200,000 fatalities and over 1 million instances of morbidity annually due to OP exposure. Phosphonate nerve agents, including sarin, soman, VX, and tabun, are extremely toxic and are considered a serious threat to national security due to their potential use in terrorist actions (See Millard, C. B.; et al., Biochem. 1999, 38, 7032; Sanson, B.; et al., J. Med. Chem. 2009, 52, 7593; Carletti, E.; et al., J. Med. Chem. 2010, 53, 4002; Masson, P.; Nachon, F.; Lockridge, O. Chem. Bio. Interact. 2010, 187, 157; and Mercey, G.; et al., Acc. Chem. Res. 2012, 45, 756).
These nerve agents elicit their acute toxicity by inhibiting the acetylcholinesterase (AChE), which results in an overstimulation of muscles due to the buildup of acetylcholine in the neuromuscular junction. The ultimate result is muscle fasciculation and subsequent cardiopulmonary arrest (Mercey, G.; et al., Acc. Chem. Res. 2012, 45, 756; and Jokanovic, M.; Prostran, M. Curr. Med. Chem. 2009, 16, 2177). Specifically, OPs inhibit AChE by covalently bonding to the serine residue in the catalytic triad of the active site (FIG. 1). The well documented and tremendous affinity of OP agents for the active cite of AChE is a result of OP's structural similarity to the tetrahedral transition state of the cognate hydrolysis reaction of acetylcholine (Quinn, D. M. Chem. Rev. 1987, 87, 955).
There are several potential treatments for both acute and chronic organophosphate poisoning. Most include a nucleophilic oxime to reactivate the enzyme along with atropine as an acetylcholine receptor antagonist and diazepam to treat seizures that arise from inhibition of AChE in the CNS (Mercey, G.; et al., Acc. Chem. Res. 2012, 45, 756; and Jokanovic, M.; Prostran, M. Curr. Med. Chem. 2009, 16, 2177). If administered shortly after exposure, the oxime (e.g. 2-pyridine aldoxime methyl chloride, 2-PAM) is able to displace the bound OP and liberate the serine residue (FIG. 1). (Kalisiak, J.; et al., J. Med. Chem. 2011, 54, 3319; Kalisiak, J.; et al., J. Med. Chem. 2012, 55, 465; Mercey, G.; et al., Chem. Commun. 2011, 47, 5295; and Sit, R. et al., J. Bio. Chem. 2011, 286, 19422.)
If administration of the oxime is delayed a process called aging occurs where the enzyme bound phosphonate experiences a solvolytic loss of an alkyl group (FIG. 1: R=isopropyl for sarin, pinacoyl for soman). See Millard, C. B.; et al., Biochem. 1999, 38, 7032; Sanson, B.; et al., J. Med. Chem. 2009, 52, 7593; Carletti, E.; et al., J. Med. Chem. 2010, 53, 4002; Masson, P.; Nachon, F.; Lockridge, O. Chem. Bio. Interact. 2010, 187, 157; and Mercey, G.; et al., Acc. Chem. Res. 2012, 45, 756. The aged adduct is a phosphonate ester monoanion, which is intrinsically less reactive as an electrophile that the erstwhile neutral phosphonate ester of the initial phosphonyl-AChE adduct. The aged adduct is further stabilized by several key interactions with the AChE active site, and is refractory to oxime reactivation. See Millard, C. B.; et al., Biochem. 1999, 38, 7032; Sanson, B.; et al., J. Med. Chem. 2009, 52, 7593; Carletti, E.; et al., J. Med. Chem. 2010, 53, 4002; and Masson, P.; Nachon, F.; Lockridge, O. Chem. Bio. Interact. 2010, 187, 157. No compounds have been reported that are able to recover AChE activity once aging has occurred, and therefore there are no known antidotes against aged AChE-OP adducts. See Mercey, G., et al., Acc. Chem. Res. 2012, 45, 756; Kalisiak, J.; et al., J. Med. Chem. 2011, 54, 3319; Kalisiak, J.; et al., J. Med. Chem. 2012, 55, 465; Mercey, G.; et al., Chem. Commun. 2011, 47, 5295; and Sit, R. et al., J. Bio. Chem. 2011, 286, 19422.
Currently there is a need for compounds and methods that can be used to reactivate the aged-AChE adduct. Such compounds and methods would be useful to counteract organophosphorus poisoning.